First Cryo-EM structure of the human TRPV4 ion-channel in the open conformation, in complex with an agonist.

In partnership with Bayer, leadXpro has generated protein and solved the cryo-EM structure of human TRPV4 in complex with the agonist 4α-PDD, providing novel information about agonist binding to this important drug target.

TRPV4 in open and closed configuration, seen along the channel axis
TRPV4 in open and closed configuration, seen along the channel axis

TRPV4 is a nonselective calcium channel that is involved in multiple physiological functions. The structure of TRPV4 in complex with 4α-PDD represents the first structural information of hTRPV4 in a ligand-induced open conformation. Complementary mutagenesis and functional assay experiments support the EM-identified binding site for 4α-PDD, and also allow the rationalisation of disruptive mutations located outside of the 4α-PDD binding site. Information about the agonist binding mode can now be used to discover and optimize novel drug candidates.

Reference:

Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation (2020-10-13).


DOI: 10.1101/2020.10.13.334797; https://www.biorxiv.org/content/10.1101/2020.10.13.334797v1.full.pdf